Patterning Genes in Retinal Development

视网膜发育中的模式基因

• 批准号: 8103931
• 负责人: Deborah L Stenkamp
• 金额: $ 33.68万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103931
• 关键词: Acute; Aging; Alleles; Award; Bioinformatics; Blindness; Bromodeoxyuridine; Cell Separation; Cells; Collection; Defect; Degenerative Disorder; Development; Embryo; Erinaceidae; Evaluation; Event; Eye; Funding; Gene Expression; Gene Expression Profile; Gene Targeting; Generations; Genes; Genetic; Goals; Grant; Health; Human; Inherited; Lead; Life; Longevity; Maintenance; Mediating; Modeling; Molecular; Molecular Genetics; Mutation; Pathology; Patients; Pattern; Phenotype; Photoreceptors; Population; Prevention; Property; Regulation; Replacement Therapy; Reporting; Research; Retina; Retinal; Retinal Cone; Retinal Diseases; Role; Signal Transduction; Stem cells; Techniques; Technology; Testing; Time; Transgenic Organisms; Transplantation; Tretinoin; Vertebrate Photoreceptors; Vision; Visual; Work; Zebrafish; age related; base; cell type; extracellular; gene replacement therapy; gene therapy; in vivo; loss of function; mutant; neurogenesis; notch protein; progenitor; research study; response; retinal damage; retinal progenitor cell; retinal rods; smoothened signaling pathway; tool; two-dimensional

DESCRIPTION (provided by applicant): The long-range objective of the proposed research is to determine the cellular and molecular events that lead to the differentiation of specific cell types in the vertebrate retina. We continue our emphasis on the roles of extracellular factors in regulating photoreceptor diversity and differentiation, as the work of the current funding period has demonstrated the significance of these factors not only for photoreceptor differentiation, but also for photoreceptor fate and for photoreceptor maintenance. Our work has provided in vivo evidence that the extracellular factor retinoic acid (RA) influences rod vs. cone neurogenesis when supplied to late retinal progenitors. In addition, RA selectively regulates the differentiation of specific photoreceptor populations when supplied later in retinal development. These regulatory functions are distinct from those of the extracellular factor Hedgehog (Hh), which is required for differentiation of all photoreceptor types, and which is required throughout the lifespan for cone photoreceptor maintenance. In the proposed award period, we will build on these studies through the evaluation of specific extracellular factors on photoreceptor fate and differentiation, examining cell-selective effects on networks of genes involved in rod and cone determination, differentiation, and in photoreceptor pathology. We apply a combination of genetic, molecular, pharmacological, histological, computational, and bioinformatics tools to the zebrafish model. We will test the following hypotheses:1) that RA and Notch signaling control rod vs. cone fate; 2) that the microenvironmental factors RA and Hh selectively manipulate cell-specific gene networks during photoreceptor differentiation; and 3) that limiting quantities of Hh signaling throughout the lifespan will engage a photoreceptor damage response. PUBLIC HEALTH RELEVANCE: Visual function requires the collaborative activities of a diverse, but properly arranged collection of specialized cells. Our goal is to understand the mechanisms that underlie the development and survival of photoreceptor cells, which are required for visual function, and which are lost in many visual degenerative diseases. Our findings will have applications for the development of photoreceptor replacement strategies and photoreceptor survival therapies, as well as for the prevention and treatment of developmental abnormalities of the retina.

描述（由申请人提供）：拟议研究的长期目标是确定导致脊椎动物视网膜中特定细胞类型分化的细胞和分子事件。我们继续强调细胞外因子在调节光感受器多样性和分化中的作用，因为当前资助期的工作已经证明了这些因素不仅对于光感受器分化，而且对于光感受器命运和光感受器维持的重要性。我们的工作提供了体内证据，表明细胞外因子视黄酸（RA）在提供给晚期视网膜祖细胞时会影响视杆细胞和视锥细胞神经发生。此外，当视网膜发育后期提供时，RA 选择性地调节特定光感受器群体的分化。这些调节功能与细胞外因子 Hedgehog (Hh) 的功能不同，后者是所有光感受器类型的分化所必需的，并且是锥体光感受器在整个生命周期中维持所需的。在拟议的奖励期内，我们将在这些研究的基础上，评估特定细胞外因素对光感受器命运和分化的影响，检查细胞选择性对参与视杆细胞和视锥细胞决定、分化以及光感受器病理学的基因网络的影响。我们将遗传、分子、药理学、组织学、计算和生物信息学工具组合应用于斑马鱼模型。我们将测试以下假设：1）RA 和 Notch 信号控制杆与锥的命运； 2）微环境因素RA和Hh在光感受器分化过程中选择性地操纵细胞特异性基因网络； 3) 在整个生命周期中限制 Hh 信号的数量将引起光感受器损伤反应。公共健康相关性：视觉功能需要多种但排列合理的专门细胞的协作活动。我们的目标是了解感光细胞发育和存活的机制，感光细胞是视觉功能所必需的，并且在许多视觉退行性疾病中会丢失。我们的研究结果将应用于开发光感受器替代策略和光感受器生存疗法，以及预防和治疗视网膜发育异常。